Development of Toll-Like Receptor Agonists as Neuroprotectants in Brain Ischemia

描述(由申请人提供)： 脑缺血预适应耐受的内源性机制是指大脑对急性缺血的反应能力，从诱导细胞损伤的信号转导到神经保护通路的诱导(耐受)。这种内源性神经保护通过Toll样受体(TLR)信号发生，TLR信号将中风后的炎症(伤害性)反应重新编程为抗炎(神经保护)反应。我们分别提供了TLR9和7的首选激动剂(CpGODN和咪喹莫特-ImQ)作为预防中风神经保护的先导化合物。尽管已经产生了可靠的啮齿动物数据，但过去和最近的翻译失败需要额外的临床前评估。因此，我们开发了一种新的灵长类中风模型来评估可能的药物治疗，并建议对我们最近发现的神经保护剂进行严格的试验，以建立基本的疗效和药代动力学数据。因此，我们的初步研究支持新的强有力的神经保护策略，用于高危中风患者，通过以下方式在非人类灵长类动物中进一步测试：目的1.确定TLR9(K-和D-Mix CpG ODN)和TLR7(ImQ)候选药物作为预防药物在NHP皮质性卒中模型中实现神经保护效果的最佳剂量。目的：在NHP皮质卒中模型中，确定K-和D-Mix CpG ODN和ImQ预防治疗的神经保护作用的时间窗。目的3.观察CpG ODN(K+D混合物)和ImQ预防老年NHP大脑皮层卒中模型的神经保护作用。目的4.探讨反复给予CpG ODN(K-和D-Mix)和ImQ预防大脑皮层卒中模型的神经保护作用。目的5.确定最佳CpG ODN(K-和D-Mix)和ImQ作为预防治疗在女性NHP皮质卒中模型中的神经保护作用。目的6.确定CpG ODN(K-和D-Mix)和ImQ作为潜在的卒中治疗药物的药代动力学和毒性。目的7.根据疗效、药代动力学和毒性特征，提交IND申请，以获得最佳的TLR候选者。 相关性：许多保护大脑免受中风的药物治疗已经尝试过，但都失败了。这项提议提供了一种基于大脑自身内源性神经保护计划的新方法。我们将研究3种已被证明对人类安全的新药，并测试它们对缺血性脑损伤的预防作用。我们将首先在相关的灵长类动物中风模型中测试这些药物，然后进入临床试验，治疗未来中风风险非常高的人类。

DESCRIPTION (provided by applicant): Endogenous mechanisms of ischemic preconditioning-tolerance have reviled the brain's ability to reprogram (precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an anti- inflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod - IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential efficacy and pharmacokinetic data. Thus our preliminary studies support new robust neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy for TLR9 (K- and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for K- and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and D mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K- and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an IND application for the optimal TLR candidate based on efficacy, pharmacokinetics and toxicity profiles. RELEVANCE: Many drug treatments to protect the brain from stroke have been tried and failed. This proposal offers a new approach based on the brain's own endogenous neuroprotective program. We will investigate 3 new drugs that have been shown to be safe in humans and test them as prophylaxis against ischemic brain injury. We will first test these drugs in a relevant primate model of stroke before moving to a clinical trial to treat humans that are at very high risk for future stroke.